The congenital disorder, CHEDDA, is associated with de novo variants that disrupt the HX repeat motif in exon 7 of ATN1. Affected individuals have recognisable facial features, profound hypotonia, nonprogressive neurocognitive impairment and variable congenital anomalies.
Individuals affected by CHEDDA have a different condition to DRPLA which is a neurodegenerative condition ascribed to polyglutamine expansions in ATN1. These distinct clinical phenotypes likely reflect differing molecular mechanisms, which in the case of CHEDDA may result in disruption of ATN1’s ability to act as a regulator of gene expression and control, eventually leading to the developmental anomalies characteristic of this disorder.
To date only 8 individuals with CHEDDA are described in the literature. We also are aware of 2 additional individuals whose variants have not been published to date. The de novo variants in the HX motif of ATN1 accounted for 1/6100 cases with a neurological phenotype who had exome sequencing through Baylor Genetics and 5/13,640 affected individuals with neurodevelopmental delay who had exome sequencing through GeneDx, suggesting a frequency of CHEDDA of between 1.6 – 3.7 x10-4 individuals with neurocognitive/neurological disorders. Despite this apparent rarity of CHEDDA, we postulate more affected individuals may have already had a variant detected in this region through genetic testing but the lack of the progressive neurological phenotype characteristic of DRPLA may have led to the variants being unreported or classified as variants of uncertain clinical significance.